Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver prevail in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations, the presence of small, dense LDL (Low Density Lipoprotein) particles and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is at present only limited awareness of the need to increase the insulin sensitivity in IRS and thus to correct the dyslipidemia which is considered to cause the accelerated progress of atherosclerosis.
Furthermore there is at present no pharmacotherapy available to adequately correct the metabolic disorders associated with IRS. To date, the treatment of type 2 diabetes mellitus has been focused on correction of the deranged control of carbohydrate metabolism associated with the disease. Stimulation of endogenous insulin secretion by means of secretagogues, like sulphonylureas, and if necessary administration of exogenous insulin are methods frequently used to normalise blood sugar but that will, if anything, further enhance insulin resistance and will not correct the other manifestations of IRS nor reduce cardiovascular morbidity and mortality. In addition such treatment involves a significant risk of hypoglycemia with associated complications.
Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as methformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficacious to a degree, their limited clinical effect is associated with side effects.
A novel therapeutic strategy involves the use of insulin sensitising agents, such as the thiazolidinediones which at least in part mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype in this class. In animal models of IRS these compounds seem to correct insulin resistance and the associated hypertriglyceridemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling, leading to enhanced insulin action in skeletal muscle, liver and adipose tissue.
Ciglitazone as well as later described thiazolidinediones in clinical development either have been discontinued reportedly due to unacceptable toxicity or show inadequate potency.
Therefore there is a need for new and better compounds with insulin sensitising properties.
Co-pending PCT application SE00/02383 discloses the use of compounds of the general formula (I) for the treatment of conditions related to insulin resistance
and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, in which formula A is situated in the ortho, meta or para position and represents
wherein    R is cyano, when X is 0, and when X is 1 then R is;            —BRa or SCORa, wherein B is O, S, SO or SO2, wherein Ra represents hydrogen, alkyl, aryl or alkylaryl and wherein the alkyl, aryl or alkylaryl group is optionally substituted one or more times by Rb, wherein Rb represents alkyl, aryl, alkylaryl, cyano, —NRcRc, ═O, halogen, —OH, —SH, -Oalkyl, -Oaryl, -Oalkylaryl, —CORc, —SRd, —SORd, or —SO2Rd, wherein Rc represents hydrogen, alkyl, aryl or alkylaryl and Rd represents alkyl, aryl or alkylaryl;        —BB1Ra, wherein B1 is O when B is S, SO or SO2 or B1 is S, SO or SO2 when B is O, and wherein B and Ra are as defined above, or alternatively R is N Ra Ra, wherein each Ra is the same or different and wherein Ra is defined above;                    R2 represents alkyl, halogen, aryl, alkylaryl, alkenyl, alkynyl, nitro or cyano and wherein the alkyl, aryl, alkenyl, alkylaryl and alkynyl group is optionally substituted by Rb, wherein Rb is as defined above;            —BRa wherein B and Ra are as defined above;                        —SO2NRaRf wherein Rf represents hydrogen, alkyl, acyl, aryl or alkylaryl and Ra is as defined above;                    —SO2ORa, wherein Ra is as defined above;            —OCONRfRa, wherein Rf and Ra are as defined above;                        —NRcCOORd, wherein Rc and Rd are as defined above;        —NRcCORa, wherein Rc and Ra are as defined above;        —CONRcRa, wherein Rc and Ra are as defined above;        —NRcSO2Rd, wherein Rc and Rd are as defined above;                    —NRcCONRaRk, wherein Ra and Rc are as defined above and Rk represents hydrogen, alkyl, aryl, or alkylaryl;            alternatively R2 is —NRcRa, wherein Rc and Ra are as defined above;            R1, R3 and R4 are the same or different and each represents hydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen or alkylaryl wherein the alkyl, aryl, alkenyl or alkynyl group is optionally substituted by Rb;            n is an integer from 1 to 6;            X is an integer 0 or 1;            m is an integer 0 or 1;            D is situated in the ortho, meta or para position and represents alkyl, acyl, aryl, alkylaryl, halogen, —CN and NO2, wherein the alkyl, aryl, or alkylaryl group is optionally substituted by Rb;                        —NRcCOORa, wherein Rc and Ra are as defined above;        —NRcCORa, wherein Rc and Ra are as defined above;                    —NRcRa, wherein Rc and Ra are as defined above;                        —NRcSO2Rd, wherein Rc and Rd are as defined above;        —NRcCONRkRc, wherein Ra, Rc and Rk are as defined above;        —NRcCSNRaRk, wherein Ra, Rc and Rk as defined above;                    —ORa, wherein Ra is as defined above;            —OSO2Rd, wherein Rd is as defined above;            —SO2Rd, wherein Rd is as defined above;                        —SORd, wherein Rd is as defined above;        —SRc, wherein Rc is as defined above;        —SO2NRaRf, wherein Rf and Ra are as defined above;                    —SO2ORa, wherein Ra is as defined above;                        —CONRcRa, wherein Rc and Ra are as defined above;        —OCONRfRa, wherein Rf and Ra are as defined above;            D′ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl,            alkylaryl, halogen, —CN, —NO2,        —NRfRb, wherein Rf and Rb are as defined above;        —ORf, wherein Rf is as defined above;        —OSO2Rd, wherein Rd is as defined above;            D″ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl,            alkylaryl, halogen, —CN, —NO2,        —NRfRb wherein Rf and Rb are as defined above;        —ORf, wherein Rf is as defined above;        —OSO2Rd, wherein Rd is as defined above.        
Compounds disclosed in this application are disclaimed from the present application.